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Antisense for the Most Common ALS Gene Corrects Cell Dysfunction

October 18, 2013

In work supported by The ALS Association and published in the scientific journal Neuron, researchers at Johns Hopkins University in Baltimore, Md., have shown that reducing the product of an ALS-causing gene mutation corrects several key problems caused by the gene. This demonstration provides support for moving this therapy forward in people with ALS whose disease is caused by mutations in this gene, called C9orf72.

“These findings provide a great deal of support for targeting the C9orf72 gene products directly, in people whose ALS is due to this gene mutation,” said Lucie Bruijn, Ph.D., Chief Scientist for The Association.

The C9orf72 gene is the most common genetic cause of ALS, accounting for more than a quarter of all familial cases and more than 5 percent of sporadic cases. The mutation is a large expansion of a six-nucleotide repeat unit, GGGGCC. The normal gene contains no more than 30 of these units, while the mutant gene may contain many dozens to hundreds of them. The mutant gene produces a long and sticky strand of RNA, which clumps together, interfering with cell function through unknown means.

In the current study, the authors used so-called antisense oligonucleotides (ASOs) to trigger degradation of the RNA aggregates. Treatment with ASOs reduced the RNA aggregates, corrected a mutation-induced pattern of aberrant gene expression, and reduced the cell’s susceptibility to overexcitation and death. The work was performed in skin cells taken from individuals with ALS and transformed into motor neurons, the cells whose death causes the disease.

The research was performed by Christopher Donnelly, Ph.D., and colleagues under the direction of Rita Sattler, Ph.D., and Jeffrey Rothstein, M.D., Ph.D., and supported through a milestone-driven drug discovery contract as part of TREAT ALS™. ISIS Pharmaceuticals is working in partnership with this study to provide the ASO’s. Academic-industry partnerships are critical to help move therapies into the clinic.

Funding for this study was made possible through The Neil Brourman, M.D. ALS Research Fund. ALS Association chapters also provide ongoing and generous support to fund The Association’s research grants. Chapters continually work with certified centers and clinics to provide the best care to people living with ALS.